Study of Pembrolizumab (MK-3475) Plus Chemotherapy Versus Placebo Plus Chemotherapy for HR+/HER2- Locally Recurrent Inoperable or Metastatic Breast Cancer (MK-3475-B49/KEYNOTE-B49)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Merck Sharp & Dohme LLC

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

5 Aug 2021 → ongoing

Decision date (initial)

2023-11-15

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Merck Sharp & Dohme LLC

External identifiers

EU CT number

2023-506752-24-00

EudraCT number

2020-005407-38

WHO UTN

U1111-1294-3354

ClinicalTrials.gov

NCT04895358

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Therapy

1. To compare pembrolizumab+chemotherapy (CT) to placebo+CT with respect to progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) as assessed by blinded independent central review (BICR) in participants with programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥1 tumors.

Secondary objectives 9

1. To compare pembrolizumab plus chemotherapy to placebo plus chemotherapy with respect to OS in participants with PDL1 CPS ≥1 tumors.
2. To compare pembrolizumab+CT to placebo+CT with respect to PFS per RECIST 1.1 as assessed by BICR in participants with CPS ≥10 tumors.
3. To compare pembrolizumab plus chemotherapy to placebo plus chemotherapy with respect to OS in participants with PDL1 CPS ≥10 tumors.
4. To compare pembrolizumab plus chemotherapy to placebo plus chemotherapy with respect to PFS per RECIST 1.1 as assessed by investigator in participants with PD-L1 CPS ≥10 and CPS ≥1 tumors, separately.
5. To compare pembrolizumab+CT to placebo+CT with respect to objective response rate (ORR) per RECIST 1.1 as assessed by BICR in participants with PD-L1 CPS ≥10 and ≥1 tumors, separately.
6. To compare pembrolizumab+CT to placebo+CT with respect to disease control rate (DCR) per RECIST 1.1 by as assessed by BICR in participants with PD-L1 CPS ≥10 and ≥1 tumors, separately.
7. To evaluate duration of response (DOR) per RECIST 1.1 as assessed by BICR in participants with PD-L1 CPS ≥10 and ≥1 tumors, separately.
8. To evaluate health-related quality of life (HRQoL) assessments using European Organization for Research and Treatment of Cancer QoL Questionnaire Core 30 (EORTC QLQ-C30) in participants with PD-L1 CPS ≥10 and ≥1 tumors, separately.
9. To evaluate safety and tolerability of pembrolizumab+CT.

Conditions and MedDRA coding

Locally recurrent inoperable or metastatic HR+/HER2- breast cancer, which has not been previously treated with cytotoxic chemotherapy in the noncurative setting

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. Has locally recurrent inoperable or metastatic HR+/HER2- breast cancer, which has not been previously treated with cytotoxic chemotherapy in the noncurative setting
2. Has progressed on prior endocrine therapy and is now a chemotherapy candidate, meeting the characteristics in regard to previous treatments of one of the following 4 groups: - Group 1: Has progressed on 2 or more lines of endocrine therapy for advanced/metastatic HR+/HER2-disease, with at least given in combination with a Cyclin-dependent kinase 4/6 (CDK4/6) inhibitor. Prior treatment with mTOR and/or PI3-K inhibitors is allowed. OR - GROUP 2a: Has progressed on 1 line of previous endocrine therapy for advanced/metastatic disease AND had a disease recurrence within 24 months of definitive surgery for the primary tumor and while on adjuvant endocrine therapy. Prior use of CDK4/6 inhibitors is required, either in the adjuvant and/or metastatic setting. Prior treatment with mTOR and/or PI3-K inhibitors is allowed. OR - GROUP 2b: Has progressed within 12 months of starting 1 line of endocrine therapy with a CDK4/6 inhibitor for advanced/metastatic HR+/HER2- disease. OR - GROUP 3: If no prior treatment with a CDK4/6 inhibitor, for advanced/metastatic disease and/or early stage disease (adjuvant), participants must have progressed within 6 months of starting 1 line of endocrine therapy with or without an mTOR or PI3-K inhibitor for metastatic disease AND had a relapse within 24 months of definitive surgery for primary tumor and while receiving adjuvant endocrine therapy.
3. Has presented a documented radiographic disease progression (as assessed by the investigator and/or histology [biopsy or cytology] for participants presenting with new metastatic lesions) during or after the last administered endocrine therapy prior to entering the study
4. Is a chemotherapy candidate that meets the criteria specified in the protocol
5. Provides a new or the last obtained core biopsy, preferably consisting of multiple cores, taken from a locally recurrent or a distant (metastatic) lesion not previously irradiated
6. Has centrally confirmed PD-L1 CPS ≥1 and HR+ (estrogen receptor [ER] and/or progesterone receptor [PgR]) /HER2- breast cancer as defined by the most recent American Society of Clinical Oncology (ASCO)/(College of American Pathologists) CAP guidelines on most recent tumor biopsy
7. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, as assessed within 7 days prior to the first dose of study treatment
8. Has adequate organ function within 10 days prior to the start of study
9. Male participants must agree to the following during the treatment period and for at least 6 months after the last dose of chemotherapy: refrain from donating sperm PLUS either be abstinent from heterosexual intercourse as their preferred and usual lifestyle or use contraception and agree to use a male condom plus partner use of an additional contraceptive
10. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: is not a woman of childbearing potential (WOCBP) OR is a WOCBP and using a highly-effective contraceptive method during the treatment period and for at least 120 days after the last dose of pembrolizumab and 180 days after the last dose of chemotherapy (whichever occurs last), AND agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction during this period
11. Has measurable disease per RECIST 1.1 as assessed by the local site investigator/radiologist
12. If receiving bisphosphonates or RANK ligand inhibitors, with stable doses for ≥4 weeks prior to the date of randomization, the participant may continue receiving this therapy during the study treatment. If participant needs to initiate these agents during the screening period, a bone scan to evaluate bone disease should be performed prior to randomization.
13. Participants who are Hepatitis B surface antigen (HBsAg) positive are eligible if they have received Hepatitis B virus (HBV) antiviral therapy for at least 4 weeks prior to the first dose of study intervention and have undetectable HBV viral load prior to randomization
14. Participants with history of Hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable at screening

Exclusion criteria 26

1. Has breast cancer amenable to treatment with curative intent
2. Has a history or current evidence of any condition (e.g., transfusion-dependent anemia or thrombocytopenia), therapy, or laboratory abnormality that is specifically contraindicated per the current locally-approved labeling, that might confound the results of the study, interfere with the participant's involvement for the full duration of the study, or is not in the best interest of the participant to be involved, in the opinion of the treating investigator
3. Has significant cardiac disease, such as: history of myocardial infarction, acute coronary syndrome, coronary angioplasty/stenting/bypass within the last 6 months, congestive heart failure (CHF) New York Heart association (NYHA) Class II-IV, or history of CHF NYHA Class III or IV
4. Has advanced/metastatic, symptomatic visceral spread at risk of rapidly evolving into life-threatening complications, such as lymphangitic lung metastases, bone marrow replacement, carcinomatous meningitis, significant symptomatic liver metastases, shortness of breath requiring supplemental oxygen, symptomatic pleural effusion requiring supplemental oxygen, symptomatic pericardial effusion, symptomatic peritoneal carcinomatosis, or the need to achieve rapid symptom control
5. Has skin only disease
6. Has a known germline BRCA mutation (deleterious or suspected deleterious) and has not received previous treatment with PARP inhibition. either in the adjuvant or metastatic setting (where available and not medically contraindicated). Single-agent PARP inhibitor therapy does not count as a line of endocrine therapy
7. Has received prior chemotherapy for locally recurrent inoperable or metastatic breast cancer
8. Has received prior therapy with an anti- programmed cell death 1 (PD-1), anti- programmed cell death ligand 1 (PD-L1), or anti- programmed cell death ligand 2 (PD-L2) agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor (e.g., cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), OX-40, CD137)
9. Has received prior systemic anticancer therapy with other investigational agents within 4 weeks prior to randomization
10. Has received prior radiotherapy within 2 weeks of start of study intervention or radiation-related toxicities requiring corticosteroids
11. Has received a live or live attenuated vaccine within 30 days prior to the first dose of study intervention
12. Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention
13. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study intervention
14. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ excluding cancer in situ of bladder that have undergone potentially curative therapy
15. Has known active central nervous system (CNS) metastases
16. Has diagnosed carcinomatous meningitis
17. Has severe hypersensitivity to pembrolizumab and/or any of its excipients or has any hypersensitivity to the planned chemotherapy agent (paclitaxel, nab-paclitaxel, liposomal doxorubicin, or capecitabine) and/or any of their excipients
18. Has an active autoimmune disease that has required systemic treatment in past 2 years
19. Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
20. Has an active infection requiring systemic therapy
21. Has a known history of Human Immunodeficiency Virus (HIV) infection
22. Has a known COVID-19 infection (symptomatic or asymptomatic)
23. Has a known history of active tuberculosis (TB)
24. Has a known psychiatric or substance abuse disorder including alcohol or drug dependency that would interfere with the participant's ability to cooperate with the requirements of the study
25. Is breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 180 days (or longer as specified by local institutional guidelines) after the last dose of study treatment
26. Has had an allogenic tissue/solid organ transplant

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) by Blinded independent Central Review (BICR) in Participants With Combined Positive Score (CPS) ≥1

Secondary endpoints 33

1. Overall Survival (OS) in Participants With CPS ≥ 1
2. PFS per RECIST 1.1 by BICR in Participants With CPS ≥10
3. Overall Survival (OS) in Participants With CPS ≥ 10
4. PFS per RECIST 1.1 by Investigator in Participants With CPS ≥10
5. PFS per RECIST 1.1 by Investigator in Participants With CPS ≥1
6. Objective Response Rate (ORR) per RECIST 1.1 by BICR in Participants With CPS ≥10
7. ORR per RECIST 1.1 by BICR in Participants With CPS ≥1
8. Disease Control Rate (DCR) per RECIST 1.1 by BICR in Participants With CPS ≥10
9. DCR per RECIST 1.1 by BICR in Participants With CPS ≥1
10. Duration of Response (DOR) per RECIST 1.1 by BICR in Participants With CPS ≥10
11. DOR per RECIST 1.1 by BICR in Participants With CPS ≥1
12. Change From Baseline in Global Health Status/Quality of Life Score on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) in Participants with CPS ≥10
13. Change From Baseline in Global Health Status/Quality of Life Score on the EORTC QLQ-C30 in Participants with CPS ≥1
14. Change From Baseline in Physical Functioning Score on the EORTC QLQ-C30 in Participants with CPS ≥10
15. Change From Baseline in Physical Functioning Score on the EORTC QLQ-C30 in Participants with CPS ≥1
16. Change From Baseline in Emotional Functioning Score on the EORTC QLQ-C30 in Participants with CPS ≥10
17. Change From Baseline in Emotional Functioning Score on the EORTC QLQ-C30 in Participants with CPS ≥1
18. Change From Baseline in Fatigue Score on the EORTC QLQ-C30 in Participants with CPS ≥10
19. Change From Baseline in Fatigue Score on the EORTC QLQ-C30 in Participants with CPS ≥1
20. Change From Baseline in Diarrhea Score on the EORTC QLQ-C30 in Participants with CPS ≥10
21. Change From Baseline in Diarrhea Score on the EORTC QLQ-C30 in Participants with CPS ≥1
22. Time to Deterioration (TTD) in Global Health Status/Quality of Life Score on the EORTC QLQ-C30 in Participants with CPS ≥10
23. TTD in Global Health Status/Quality of Life Score on the EORTC QLQ-C30 in Participants with CPS ≥1
24. TTD in Physical Functioning Score on the EORTC QLQ-C30 in Participants with CPS ≥10
25. TTD in Physical Functioning Score on the EORTC QLQ-C30 in Participants with CPS ≥1
26. TTD in Emotional Functioning Score on the EORTC QLQ-C30 in Participants with CPS ≥10
27. TTD in Emotional Functioning Score on the EORTC QLQ-C30 in Participants with CPS ≥1
28. TTD in Fatigue Score on the EORTC QLQ-C30 in Participants with CPS ≥10
29. TTD in Fatigue Score on the EORTC QLQ-C30 in Participants with CPS ≥1
30. TTD in Diarrhea Score on the EORTC QLQ-C30 in Participants with CPS ≥10
31. TTD in Diarrhea Score on the EORTC QLQ-C30 in Participants with CPS ≥1
32. Percentage of Participants who Experience an Adverse Event (AE)
33. Percentage of Participants who Discontinue Study Drug due to an AE

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 2

Auxiliary 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Merck Sharp & Dohme LLC

Sponsor organisation

Merck Sharp & Dohme LLC

Address

126 East Lincoln Avenue

City

Rahway

Postcode

07065-4607

Country

United States

Scientific contact point

Organisation

Merck Sharp & Dohme LLC

Contact name

Paolo D'Amico

Public contact point

Organisation

Merck Sharp & Dohme LLC

Contact name

Paolo D'Amico

Third parties 10

Locations

13 EU/EEA countries · 67 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 112 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

14 submissions — initial application plus substantial / non-substantial modifications